DESCRIPTION: MAP kinases have provided the focal point for remarkably rapid advances in our understanding of the control of cellular events by growth factor and cytokine receptors. The applicant began the last granting period having just cloned the closely related MAP kinases, ERK1 and ERK2. The isolation of these clones accelerated discoveries of upstream mammalian enzymes. ERK1 and ERK2 are the terminal enzymes in a three-kinase cascade, called a MAP kinase module. The module consists of Raf isoforms which activate the MAPERK kinases (MEK), MEK1 and MEK2, which in turn activate ERK1 and ERK2. The existence of other three-kinase cascades composed of functional homologs (MEKK-MEK-ERK) indicates that MAP kinase modules have been adapted for interpretation of many extracellular signals and the subsequent regulation of cellular events. The applicant will focus on the prototypic MAP kinase module, the MAP kinase cascade, to elucidate and predict biochemical mechanisms that regulate this and other MAP kinase modules. The applicant proposes to: 1) characterize mechanisms of nuclear translocation of MAP kinases; 2) elucidate upstream regulation of the ERK/MAP kinase pathway by insulin and G protein-coupled receptors; and 3) define mechanisms and factors maintaining specificity within the ERK/MAP kinase pathway. In addition, the applicant will identify and study novel MAP kinase pathways terminating in the ERK family member ERK3 and that encompass novel MEKs for which she has isolated cDNAs.